SETD2 is the main transferase for the trimethylation of histone H3 at lysine 36 (H3K36me3) in mammals. SETD2 plays important role in repairing DNA double strand breaks and maintaining chromatin integrity. In renal carcinoma, SETD2 deficiency caused DNA replication fork instability and DNA damage. The absence of SETD2 was also reported to have strong tumor-promoting effects in lung adenocarcinomas (LUAD). However, the other roles of SETD2 remain poorly understood in LUAD. In this study, we utilized comprehensive omics-data analysis to determine that SETD2 was associated with DNA damage and immunerelated signals in LUAD.SETD2 knockdown induced DNA damage and cGAS activation in LUAD cells, and reduced the number of cells at the G1 phase. Moreover, SETD2 deficiency was conducive to mutation burden, immune cellinfiltration, and immunotherapy responses. High SETD2 expression was associated with highradio-curability. These findings suggest that SETD2 may be a promising biomarker of therapeutic responses for LUAD patients, and offer novel insights into immunotherapy and radiotherapy.